Chronic pain is a major clinical problem that has a profound effect on quality of life and poses a significant burden on the U.S. health care system. Available treatments are not always effective: a substantial proportion of patients report inadequate management of pain and are often plagued by deleterious side effects. It is known that proinflammatory mediators released by immune cells contribute to sensitization of nociceptors in response to injury, suggesting that modification of inflammatory pathways contributes to the development of persistent pain, although the precise mechanisms have thus far eluded detection. To date, most attention has been focused on neuro- immune interactions at the site of injury in peripheral tissues while largely ignoring immune mediation at the level of the sensory ganglia. Our preliminary results indicate that resident macrophages are present in naive DRG and that macrophage phenotype changes in response to nociceptor activity within the ganglion. These findings suggest the exciting possibility that resident macrophages respond to nociceptor activity in DRG in response to a distant insult, supporting a novel mechanism and site of action for neuro-immune interactions that may regulate nociceptor sensitivity. With this support, we will evaluate the role of DRG macrophages in response to peripheral nociceptor activation in vitro and in vivo in wildtype and macrophage deficient animals. This will be performed using both inflammatory pain models as well as neuropathic pain models in addition to multiple species to directly assess immune input in the development of persistent pain relevant to the human condition. Further, these studies will provide a platform to analyze the ganglionic macrophage response to cannabinoid receptor 2 agonists and allow us to determine whether the antinociceptive properties of these compounds are mediated by the peripheral immune system. Together, these studies will provide a strong foundation for an NIH R01 submission to examine the impact of DRG macrophages on nociceptor response properties in both healthy animals and models of chronic pain. Experiments proposed here will: 1) characterize the phenotype of resident macrophages in DRG and determine the profile of macrophage cytokine expression, and 2) demonstrate the function of DRG macrophages in peripheral pain models and in response to CB2 agonists. These data are critical for determining whether DRG macrophages significantly contribute to nociceptor sensitization, thus contributing to the development of persistent pain. Experimental results obtained here will be submitted for publication in a peer reviewed journal and will form the basis of an extramural funding application with the ultimate goal of developing novel approaches for the treatment of chronic pain.